CA2518932A1 - 2,4-di(phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders - Google Patents
2,4-di(phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders Download PDFInfo
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- CA2518932A1 CA2518932A1 CA002518932A CA2518932A CA2518932A1 CA 2518932 A1 CA2518932 A1 CA 2518932A1 CA 002518932 A CA002518932 A CA 002518932A CA 2518932 A CA2518932 A CA 2518932A CA 2518932 A1 CA2518932 A1 CA 2518932A1
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- unsubstituted
- substituted
- c8alkyl
- hydrogen
- c8alkoxy
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- 201000010099 disease Diseases 0.000 title claims abstract 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract 10
- 208000026278 immune system disease Diseases 0.000 title claims abstract 8
- 230000001613 neoplastic effect Effects 0.000 title claims abstract 5
- 230000002757 inflammatory effect Effects 0.000 title claims abstract 4
- 208000027866 inflammatory disease Diseases 0.000 title claims abstract 3
- GKFFFOLFBJUEFN-UHFFFAOYSA-N 2-n,4-n-diphenylpyrimidine-2,4-diamine Chemical class C=1C=NC(NC=2C=CC=CC=2)=NC=1NC1=CC=CC=C1 GKFFFOLFBJUEFN-UHFFFAOYSA-N 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 claims abstract 5
- 239000003814 drug Substances 0.000 claims abstract 4
- 238000000034 method Methods 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 49
- 239000001257 hydrogen Substances 0.000 claims 49
- -1 C2-C8alkinyl Chemical group 0.000 claims 39
- 150000002431 hydrogen Chemical group 0.000 claims 33
- 150000001875 compounds Chemical class 0.000 claims 23
- 229910052736 halogen Inorganic materials 0.000 claims 20
- 150000002367 halogens Chemical class 0.000 claims 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 17
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 16
- 125000005842 heteroatom Chemical group 0.000 claims 16
- 125000000623 heterocyclic group Chemical group 0.000 claims 16
- 229910052760 oxygen Inorganic materials 0.000 claims 16
- 229910052717 sulfur Inorganic materials 0.000 claims 16
- 125000001424 substituent group Chemical group 0.000 claims 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 13
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 11
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims 9
- 229910052799 carbon Inorganic materials 0.000 claims 8
- 229910052757 nitrogen Inorganic materials 0.000 claims 8
- 150000003839 salts Chemical class 0.000 claims 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 7
- 125000001246 bromo group Chemical group Br* 0.000 claims 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims 5
- 125000001153 fluoro group Chemical group F* 0.000 claims 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims 3
- 230000002265 prevention Effects 0.000 claims 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 2
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 2
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 229940088679 drug related substance Drugs 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 230000002062 proliferating effect Effects 0.000 claims 2
- UWMGQQWDXJETSN-UHFFFAOYSA-N 2-[[5-bromo-2-(2-methoxy-5-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-n-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC=C(C=2)N2CCOCC2)OC)=NC=C1Br UWMGQQWDXJETSN-UHFFFAOYSA-N 0.000 claims 1
- UIURJGHFUQVQKB-UHFFFAOYSA-N 2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]-n-propan-2-ylbenzenesulfonamide Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1S(=O)(=O)NC(C)C UIURJGHFUQVQKB-UHFFFAOYSA-N 0.000 claims 1
- UYJNQQDJUOUFQJ-UHFFFAOYSA-N 2-[[5-chloro-2-[2-methoxy-4-(4-morpholinyl)anilino]-4-pyrimidinyl]amino]-N-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCOCC2)OC)=NC=C1Cl UYJNQQDJUOUFQJ-UHFFFAOYSA-N 0.000 claims 1
- IWBUGKWDHWHLCF-UHFFFAOYSA-N 2-[[5-chloro-2-[4-[3-(methylamino)pyrrolidin-1-yl]anilino]pyrimidin-4-yl]amino]-n-propan-2-ylbenzenesulfonamide Chemical compound C1C(NC)CCN1C(C=C1)=CC=C1NC1=NC=C(Cl)C(NC=2C(=CC=CC=2)S(=O)(=O)NC(C)C)=N1 IWBUGKWDHWHLCF-UHFFFAOYSA-N 0.000 claims 1
- ZDCPYKDNLZEPSX-UHFFFAOYSA-N 5-chloro-2-n-[2-methoxy-4-(4-piperidin-1-ylpiperidin-1-yl)phenyl]-4-n-(2-propylsulfonylphenyl)pyrimidine-2,4-diamine Chemical compound CCCS(=O)(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCC(CC2)N2CCCCC2)OC)=NC=C1Cl ZDCPYKDNLZEPSX-UHFFFAOYSA-N 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 claims 1
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 claims 1
- 206010020751 Hypersensitivity Diseases 0.000 claims 1
- 102000038455 IGF Type 1 Receptor Human genes 0.000 claims 1
- 108010031794 IGF Type 1 Receptor Proteins 0.000 claims 1
- 210000001744 T-lymphocyte Anatomy 0.000 claims 1
- 206010052779 Transplant rejections Diseases 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 208000026935 allergic disease Diseases 0.000 claims 1
- 230000007815 allergy Effects 0.000 claims 1
- 210000003719 b-lymphocyte Anatomy 0.000 claims 1
- 210000000481 breast Anatomy 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 210000004443 dendritic cell Anatomy 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 210000003979 eosinophil Anatomy 0.000 claims 1
- 230000002496 gastric effect Effects 0.000 claims 1
- 210000003630 histaminocyte Anatomy 0.000 claims 1
- 210000002865 immune cell Anatomy 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 210000002540 macrophage Anatomy 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 230000001537 neural effect Effects 0.000 claims 1
- 201000008968 osteosarcoma Diseases 0.000 claims 1
- 230000002611 ovarian Effects 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 abstract 1
- 150000003230 pyrimidines Chemical class 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Novel pyrimidine derivatives of formula (I), to processes for their production, their use as pharmaceuticals in the treatment of neoplastic diseases, inflammatory and immune system disorders and to pharmaceutical compositions comprising them.
Claims (22)
1. A compound of formula I
wherein each of R0, R1, R2,and R3 independently is hydrogen, C1-C8alkyl, C1-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, aminoC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S, hydroxy, C1-C8alkoxy, hydroxyC1-C8alkoxy, C1-C8alkoxyC1-C8alkoxy, haloC1-C8alkoxy, unsubstituted or substituted C5-C10arylC1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstitued or substituted amino, C1-C8alkylthio, C1-C8alkylsulfinyl, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, C1-C8alkoxycarbonyl, unsubstitued or substituted carbamoyl, unsubstitued or substituted sulfamoyl, cyano or nitro;
or R0 and R1, R1 and R2, and/or R2 and R3 form, together with the carbon atoms to which they are attached, a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1,
wherein each of R0, R1, R2,and R3 independently is hydrogen, C1-C8alkyl, C1-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, aminoC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S, hydroxy, C1-C8alkoxy, hydroxyC1-C8alkoxy, C1-C8alkoxyC1-C8alkoxy, haloC1-C8alkoxy, unsubstituted or substituted C5-C10arylC1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstitued or substituted amino, C1-C8alkylthio, C1-C8alkylsulfinyl, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, C1-C8alkoxycarbonyl, unsubstitued or substituted carbamoyl, unsubstitued or substituted sulfamoyl, cyano or nitro;
or R0 and R1, R1 and R2, and/or R2 and R3 form, together with the carbon atoms to which they are attached, a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1,
2 or 3 heteroatoms selected from N, O and S;
R4 is hydrogen or C1-C8alkyl;
each of R5 and R6 independently is hydrogen, C1-C8alkyl, C1-C8alkoxyC1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, halogen, carboxy, C1-C8alkoxycarbonyl, unsubstitued or substituted carbamoyl, cyano, or nitro; and each of R7, R8, R9, and R10 independently is C1-C8alkyl, C2-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, aminoC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-c10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S, hydroxy, C1-C8alkoxy, hydroxyC1-C8alkoxy, C1-C8alkoxyC1-C8alkoxy, haloC1-C8alkoxy, unsubstituted or substituted C5-C10arylC1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstitued or substituted amino, C1-C8alkylthio, C1-C8alkylsulfinyl, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, C1-C8alkoxycarbonyl, unsubstitued or substituted carbamoyl, unsubstitued or substituted sulfamoyl, cyano or nitro;
wherein R7, R8 and R9 independently of each other can also be hydrogen;
or R7 and R8, R8 and R9, and/or R9 and R10 form together with the carbon atoms to which they are attached, a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1, 2 or 3 heteroatoms selected from N, O and S;
A is C or N;
and salts thereof.
2. A compound of formula I according to claim 1, wherein each of R0 or R2 independently is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl;
R1 is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, haloC1-C9alkoaxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl;
R3 is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, C1-C8alkoxy, substituted amino, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, substituted or unsubstituted carbamoyl, unsubstituted or substituted sulfamoyl; or each pair of adjacent substituents R0 and R1, or R1 and R2, or R2 and R3 is -CH2-NH-CO-, -CH2-CH2-NH-CO-, -CH2-CO-NH-, -CH2-CH2-CO-NH-, -CH2-NH-SO2-, -CH2-CH2-NH-SO2-, -CH2-SO2-NH-, -CH2-CH2-SO2-NH-, -CH2-CH2-SO2-, -CH2-CH2-CH2-SO2-, -O-CH2-O-, or -O-O-, and such pairs wherein hydrogen in NH is replaced by C1-C8alkyl;
R4 is hydrogen or C1-C8alkyl;
R5 is hydrogen; C1-C8alkyl, halogen, haloC1-C8alkyl, cyano or nitro;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl;
R6 is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl, cyano, or nitro; and R10 is C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, carboxy, carbamoyl, or unsubstituted or substituted sulfamoyl; or each pair of adjacent substituents R7 and R8, or R8 and R9 or R9 and R10, is -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-O--CH=CH-O-, -O-CH2-O-, or -O-CF2-O-;
A is C or N.
R4 is hydrogen or C1-C8alkyl;
each of R5 and R6 independently is hydrogen, C1-C8alkyl, C1-C8alkoxyC1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, halogen, carboxy, C1-C8alkoxycarbonyl, unsubstitued or substituted carbamoyl, cyano, or nitro; and each of R7, R8, R9, and R10 independently is C1-C8alkyl, C2-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, aminoC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-c10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S, hydroxy, C1-C8alkoxy, hydroxyC1-C8alkoxy, C1-C8alkoxyC1-C8alkoxy, haloC1-C8alkoxy, unsubstituted or substituted C5-C10arylC1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstitued or substituted amino, C1-C8alkylthio, C1-C8alkylsulfinyl, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, C1-C8alkoxycarbonyl, unsubstitued or substituted carbamoyl, unsubstitued or substituted sulfamoyl, cyano or nitro;
wherein R7, R8 and R9 independently of each other can also be hydrogen;
or R7 and R8, R8 and R9, and/or R9 and R10 form together with the carbon atoms to which they are attached, a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1, 2 or 3 heteroatoms selected from N, O and S;
A is C or N;
and salts thereof.
2. A compound of formula I according to claim 1, wherein each of R0 or R2 independently is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl;
R1 is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, haloC1-C9alkoaxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl;
R3 is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, C1-C8alkoxy, substituted amino, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, substituted or unsubstituted carbamoyl, unsubstituted or substituted sulfamoyl; or each pair of adjacent substituents R0 and R1, or R1 and R2, or R2 and R3 is -CH2-NH-CO-, -CH2-CH2-NH-CO-, -CH2-CO-NH-, -CH2-CH2-CO-NH-, -CH2-NH-SO2-, -CH2-CH2-NH-SO2-, -CH2-SO2-NH-, -CH2-CH2-SO2-NH-, -CH2-CH2-SO2-, -CH2-CH2-CH2-SO2-, -O-CH2-O-, or -O-O-, and such pairs wherein hydrogen in NH is replaced by C1-C8alkyl;
R4 is hydrogen or C1-C8alkyl;
R5 is hydrogen; C1-C8alkyl, halogen, haloC1-C8alkyl, cyano or nitro;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl;
R6 is hydrogen, C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl, cyano, or nitro; and R10 is C1-C8alkyl, hydroxyC1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, carboxy, carbamoyl, or unsubstituted or substituted sulfamoyl; or each pair of adjacent substituents R7 and R8, or R8 and R9 or R9 and R10, is -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-O--CH=CH-O-, -O-CH2-O-, or -O-CF2-O-;
A is C or N.
3. A compound of formula l according to claim 1, Wherein each of R0 or R2 independently is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, or halogen;
R1 is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen;
R3 is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, C1-C8alkoxy, substituted amino, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, substituted or unsubstituted carbamoyl, or unsubstituted or substituted sulfamoyl; or each pair of adjacent substituents R0 and R1, or R1 and R2, or R2 and R3 is -CH2-NH-CO-, -CH2 NH-SO2-, -CH2-CH2-SO2-, -O-CH2-O-, or -O-CF2-O-, and such pairs wherein hydrogen in NH is replaced by C1-C8alkyl;
R4 is hydrogen;
R5 is hydrogen, halogen, haloC1-C8alkyl, or nitro;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted carbamoyl, or unsubstituted or substituted sulfamoyl;
R8 is hydrogen, C1-C8alkyl, haloC1-C8alkyl, C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted sulfamoyl, or nitro; and R10 is C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, or halogen; or each pair of adjacent substituents R7 and R8, or R8 and R9 or R9 and R10, is -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-O-, or -O-CF2-O-;
A is C or N.
R1 is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen;
R3 is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, C1-C8alkoxy, substituted amino, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, substituted or unsubstituted carbamoyl, or unsubstituted or substituted sulfamoyl; or each pair of adjacent substituents R0 and R1, or R1 and R2, or R2 and R3 is -CH2-NH-CO-, -CH2 NH-SO2-, -CH2-CH2-SO2-, -O-CH2-O-, or -O-CF2-O-, and such pairs wherein hydrogen in NH is replaced by C1-C8alkyl;
R4 is hydrogen;
R5 is hydrogen, halogen, haloC1-C8alkyl, or nitro;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted carbamoyl, or unsubstituted or substituted sulfamoyl;
R8 is hydrogen, C1-C8alkyl, haloC1-C8alkyl, C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted sulfamoyl, or nitro; and R10 is C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, or halogen; or each pair of adjacent substituents R7 and R8, or R8 and R9 or R9 and R10, is -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-O-, or -O-CF2-O-;
A is C or N.
4. A compound of formula I according to claim 1, wherein each of R0or R2 independently is hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy;
R1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2-morpholinoethoxy;
R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or the pair of adjacent substituents R0 and R1, or R1 and R2 is -O-CH2-O-, or the pair of adjacent substituents R2 and R3 is -CH2-NH-CO- or -CH2-NH-SO2-;
R4 is hydrogen;
R5 is hydrogen, chloro, bromo, trifluoromethyl or nitro;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted carbamoyl, or unsubstituted or substituted sulfamoyl;
R8 is hydrogen, C1-C8alkyl, haloC1-C8alkyl, C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted sulfamoyl, or nitro; and R10 is C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, or halogen; or each pair of adjacent substituents R7 and R8, or R8 and R9 or R9 and R10, is -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-O-, or -O-CF2-O-;
A is C or N.
R1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2-morpholinoethoxy;
R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or the pair of adjacent substituents R0 and R1, or R1 and R2 is -O-CH2-O-, or the pair of adjacent substituents R2 and R3 is -CH2-NH-CO- or -CH2-NH-SO2-;
R4 is hydrogen;
R5 is hydrogen, chloro, bromo, trifluoromethyl or nitro;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, C1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted carbamoyl, or unsubstituted or substituted sulfamoyl;
R8 is hydrogen, C1-C8alkyl, haloC1-C8alkyl, C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C8alkoxy, haloC1-C8alkoxy, C5-C10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted sulfamoyl, or nitro; and R10 is C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, or halogen; or each pair of adjacent substituents R7 and R8, or R8 and R9 or R9 and R10, is -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-O-, or -O-CF2-O-;
A is C or N.
5. A compound of formula I according to claim 1, wherein each of R0 or R2 independently is hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy;
R1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2-morpholinoethoxy;
R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or the pair of adjacent substituents R0 and R1, or R1 and R2 is -O-CH2-O-, or the pair of adjacent substituents R2 and R3 is -CH2-NH-CO- or -CH2-NH-SO2-;
R4 is hydrogen;
R5 is hydrogen, chloro, bromo, trifluoromethyl or nitro;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m-or p-methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;
R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R10 is methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-O- or the pair of adjacent substituents R9 and R10 is -NH-CH=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-or -O-CF2-O-;
A is C or N.
R1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2-morpholinoethoxy;
R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or the pair of adjacent substituents R0 and R1, or R1 and R2 is -O-CH2-O-, or the pair of adjacent substituents R2 and R3 is -CH2-NH-CO- or -CH2-NH-SO2-;
R4 is hydrogen;
R5 is hydrogen, chloro, bromo, trifluoromethyl or nitro;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m-or p-methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;
R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R10 is methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-O- or the pair of adjacent substituents R9 and R10 is -NH-CH=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-or -O-CF2-O-;
A is C or N.
6. A compound of formula I according to claim 1, wherein each of R0, R1 or R2 is hydrogen;
R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl;
R4 is hydrogen;
R5 is chloro or bromo;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m-or p-methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;
R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R10 is methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-O-, or the pair of adjacent substituents R9 and R10 is -NH-CH=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-or -O-CF2-O-;
A is C or N.
R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl;
R4 is hydrogen;
R5 is chloro or bromo;
R6 is hydrogen;
each of R7 and R9 independently is hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m-or p-methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;
R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R10 is methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-O-, or the pair of adjacent substituents R9 and R10 is -NH-CH=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-or -O-CF2-O-;
A is C or N.
7. The compound of formula I according to claim 1, wherein each of R0, R1 or R2 is hydrogen, R3 is methylsulfamoyl, R4 is hydrogen, R5 is bromo, R6 is hydrogen, each of R7 and R8 is methoxy, R9 is hydrogen, and R10 is methyl, and A is C or N.
8. The compound of formula I according to claim 1, wherein each of R0, R1 or R2 is hydrogen, R3 is methylsulfamoyl, R4 is hydrogen, R5 is bromo, R6 is hydrogen, each of R7 and R8 is hydrogen, and the pair of adjacent substituents R9 and R10 is -CH2-CH2-CH2-, and A is C or N.
9. The compound of formula 2-{5-Chloro-2-[4-(3-methylamino-pyrrolidin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-N-isopropyl-benzenesulfonamide.
10. A process for the production of a compound of formula I according to claim 1, comprising reacting a compound of formula II
wherein R0, R1, R2, R3, R4, R5, and R6 are as defined in claim 1, and Y is a leaving group, with a compound of formula III
wherein R7, R8, R9 and R10 are as defined in claim 1;
and, if desired, converting a compound of formula I, wherein the substituents have the meaning as defined in claim 1, into another compound of formula I as defined in claim 1;
and recovering the resulting compound of formula I in free from or as a salt, and, when required, converting the compound of formula I obtained in free form into the desired salt, or an obtained salt into the free form.
wherein R0, R1, R2, R3, R4, R5, and R6 are as defined in claim 1, and Y is a leaving group, with a compound of formula III
wherein R7, R8, R9 and R10 are as defined in claim 1;
and, if desired, converting a compound of formula I, wherein the substituents have the meaning as defined in claim 1, into another compound of formula I as defined in claim 1;
and recovering the resulting compound of formula I in free from or as a salt, and, when required, converting the compound of formula I obtained in free form into the desired salt, or an obtained salt into the free form.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, as active ingredient together with one or more pharmaceutically acceptable diluents or carriers.
12. The use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment or prevention of neoplastic diseases and immune system disorders.
13. A combination comprising a therapeutically effective amount a compound according to any one of claims 1 to 9 and one or more further drug substances, said further drug substance being useful in the treatment of neoplastic diseases or immune system disorders.
14. A method for the treatment of neoplastic diseases and immune system disorders in a subject in need thereof which comprises administering an effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition comprising same.
15. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease which responds to inhibition of focal adhesion kinase or/and IGF-1 Receptor.
16. The use according to claim 15, wherein the disease to be treated is selected from proliferative disease.
17. The use according to claim 16, wherein the proliferative disease to be treated is selected from a tumor of, breast, renal , prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastro-intestinal tumours as well as osteosarcomas and melanomas.
18. The use according to claim 15, wherein the disease to be treated is an immune disease.
19. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of inflammatory and/or an immune disorder.
20. Use according to claim 19 wherein the inflammatory and/or immune disorder is selected from transplant rejection, allergy and autoimmune disorders mediated by immune cells including T lymphocytes, B lymphocytes, macrophages, dendritic cells, mast cells and eosinophils.
21. The use according to any one of claims 14 to 19, wherein the compound is 2-[5-Bromo-2-(2-methoxy-5-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide or a pharmaceutically acceptable salt thereof.
22. The use according to any one of claims 14 to 19, wherein the compound is selected from 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide, N2-(4-[1,4']Bipiperidinyl-1'-yl-2-methoxy-phenyl)-5-chloro-N4-[2-(propane-1-sulfonyl)-phenyl]-pyrimidine-2,4-diamine and 2-{5-Chloro-2-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-N-isopropyl-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.
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